Local administration of gallium compositions to treat pain

ABSTRACT

Provided are methods of treating pain, including neuropathic pain, in human and veterinary individuals. These methods employ locally administrable pharmaceutical gallium compositions, including pharmaceutical gallium compositions suitable for administration to the skin and mucous membranes. The compositions comprise pharmaceutically acceptable gallium compounds, such as gallium maltolate or gallium nitrate, together with pharmaceutically acceptable carriers suitable for local administration, including those suitable for topical administration. The administration of such compositions provides relief from pain, itching, allodynia, hyperalgesia, and related symptoms.

CROSS REFERENCE TO RELATED PATENT APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/960,025 filed on Aug. 6, 2013, which is a continuation of U.S.application Ser. No. 13/648,577, filed Oct. 10, 2012, now U.S. Pat. No.8,506,990, which is a continuation of U.S. application Ser. No.13/419,700, filed Mar. 14, 2012, now U.S. Pat. No. 8,293,268, which is acontinuation of U.S. application Ser. No. 11/936,607, filed Nov. 7,2007, now U.S. Pat. No. 8,168,214, which claims priority under 35 U.S.C.§119(e) to U.S. Provisional Application No. 60/858,182, filed on Nov. 9,2006, the disclosure of each application being incorporated by referenceherein in its entirety.

TECHNICAL FIELD

This invention relates generally to treatments for pain, includingneuropathic pain. In particular, this invention pertains topharmaceutical gallium compositions and their uses in treating pain bylocal administration.

BACKGROUND OF THE INVENTION

Gallium compounds, including gallium nitrate, gallium sulfate, andgallium maltolate, have been repeatedly shown to have anti-inflammatoryactivities when administered systemically (i.e., orally, intravenously,or by other means that introduce gallium into the bloodstream and allowfor its distribution through the body). Particular efficacy for galliumhas been reported in animal models of rheumatoid arthritis (Delbarre F,Rabaud M, COMPTES RENDUS DE L=ACAD{acute over (E)}MIE DES SCIENCES,SERIES D 283:1469-1472, 1976; Matkovic Vet al., CURRENT THERAPEUTICRESEARCH 50:255-267, 1991; U.S. Pat. No. 5,175,006 to Matkovic et al.),multiple sclerosis (Whitacre C et al., JOURNAL OF NEUROIMMUNOLOGY39:175-182, 1992), uveitis (Lobanoff M C et al., EXPERIMENTAL EYERESEARCH 65:797-801, 1997), and Type 1 diabetes (Flynn J O et al.,DIABETES 41:38A, 1992). Systemically administered gallium has also shownefficacy in the treatment of cancer and infectious disease (Bernstein LR, PHARMACOLOGICAL REVIEWS 50:665-682, 1998). Locally administeredgallium is effective in treating psoriasis and related dermatologicdisorders (U.S. Pat. No. 5,747,482 to Bernstein). It has now beensurprisingly discovered that locally administered gallium can reducepain, itching, allodynia, hyperalgesia, and related symptoms.

Locally administered gallium is particularly effective in relievingneuropathic symptoms, especially peripheral neuropathic pain. Peripheralneuropathic pain is apparently caused by damage to peripheral neurons,and is typically characterized as “burning,” “shooting,” “stabbing,” or“electric-shock-like.” It may occur without external stimulation or,very commonly, it may be manifested as allodynia (an experience of painfrom normally non-painful stimuli, such as from light touching) orhyperalgesia (an exaggerated sense of pain from a normally painfulstimulation). The pain can be very intense and disabling; the pain fromtrigeminal neuralgia (neuropathy of the trigeminal nerve) is consideredamong the most severe types of pain known.

At least two million adults are estimated to have neuropathic pain inthe United States, with the great majority having peripheral rather thancentral neuropathic pain (Morely-Forster P, PAIN RESEARCH MANAGEMENT 11Suppl A:5A-10A, 2006). Some of the most common causes of peripheralneuropathic pain are diabetes, HIV infection, postherpetic neuralgia,trigeminal neuralgia, cancer, and cancer treatments. Numerous othercauses of peripheral neuropathic pain are also known, including trauma,non-HIV infections, drugs, toxins, surgery, and complex regional painsyndrome (also called causalgia or reflex sympathetic dystrophysyndrome). The etiology for many cases of peripheral neuropathic pain isnever discovered. Some of the common causes of peripheral neuropathicpain are summarized below.

Painful diabetic neuropathy: Diabetes afflicts about 21 million peoplein the United States (National Institute of Diabetes and Digestive andKidney Diseases, NATIONAL DIABETES STATISTICS FACT SHEET: GENERALINFORMATION AND NATIONAL ESTIMATES ON DIABETES IN THE UNITED STATES,2005) and nearly 200 million people worldwide (Wild S et al., DIABETESCARE 27:1047-1053, 2004). Painful diabetic neuropathy is estimated toaffect approximately 20-24% of diabetics, with pain being defined as arecording by the patient of at least 10 mm on a 100 mm visual analogpain scale (Schmader K E, THE CLINICAL JOURNAL OF PAIN 18:350-354,2002). The pain occurs most commonly in the extremities.

Cancer and cancer-associated iatrogenic neuropathic pain: Neuropathicpain is estimated to afflict about a third of cancer patients (Davis MP, Walsh D, AMERICAN JOURNAL OF HOSPICE PALLIATIVE CARE 21:137-142,2004). In most cases the neuropathic pain is due to tumor tissueinfiltrating or pressing on neurons, with other causes including nervedamage caused by surgery, chemotherapy, or radiotherapy. Treatments forbreast cancer are particularly likely to cause neuropathic pain: nearly50% of patients experience chronic pain following surgery for breastcancer, with most of the pain being neuropathic (Morely-Forster P, PAINRESEARCH MANAGEMENT 11 Suppl A:5A-10A, 2006).

HIV-infection related neuropathic pain: Neuropathic pain, generally dueto distal sensory polyneuropathy, is estimated to afflict at least athird of those infected with HIV (Luciano C A et al., CURRENT OPINION INNEUROLOGY 16:403-409, 2003). The cause is not always known, but may bedue to HIV infection of neurons, the release of neurotoxins bymacrophages, toxic reactions to drugs, opportunistic infections, ornutrient deficiencies. Neuropathic pain associated with HIV infectionappears to be an under-recognized and under-treated condition.

Postherpetic neuralgia: Herpes zoster infection (shingles) is estimatedto strike about 800,000 people each year in the United States (SchmaderK E, THE CLINICAL JOURNAL OF PAIN 18:350-354, 2002). Pain associatedwith shingles is itself neuropathic, at least in part. The incidence ofsubsequent postherpetic neuralgia (nearly always a peripheralneuropathy) is directly correlated with age and with the severity of theherpetic rash. For herpes zoster patients over 50 years old (the greatmajority of herpes zoster patients), postherpetic neuralgia occurs in50-68% one month after rash healing, in 25-50% three months after rashhealing, and in 15-35% six months after rash healing (the lower numbersbeing for those treated with antiviral drugs) (Schmader K E, THECLINICAL JOURNAL OF PAIN 18:350-354, 2002).

Peripheral neuropathic pain is clearly a widespread medical problem,occurring in millions of people worldwide, resulting from a wide rangeof causes.

Current Treatments for Peripheral Neuropathic Pain

Current preferred therapies for peripheral neuropathic pain includesystemic antidepressants (particularly tricyclic antidepressants),anticonvulsants (including carbamazepine and gabapentin), opioidanalgesics (including oxycodone, methadone, and dextromethorphan), andtopical lidocaine and capsaicin. Few of these treatments produce evenmoderate pain relief for half the patients receiving them.

Antidepressants: Antidepressants are commonly the first choice fortreating neuropathic pain. A recent survey of the literature (Saarto T,Wiffen P J, THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS2005(3):CD005454, 2005) found that tricyclic antidepressants were themost effective, with amitriptyline being particularly effective.Amitriptyline, however, had an NNT (number needed to treat) value of 2for moderate pain relief (that is, only 50% of those treated had atleast moderate pain relief). In general, moderate pain relief forperipheral neuropathic pain was produced by tricyclic antidepressants inabout 33-50% of patients, by serotonin noradrenaline reuptake inhibitorsin about 20-25% of patients, and by selective serotonin reuptakeinhibitors in about 14% of patients (Sindrup S H et al., BASIC &CLINICAL PHARMACOLOGY & TOXICOLOGY 96:399-409, 2005).

Anticonvulsants: A number of anticonvulsants have been administered forthe treatment of peripheral neuropathic pain, with gabapentin,carbamazepine, and phenytoin appearing to be the most effective. Again,however, the efficacy rates are fairly low. For moderate pain relief,gabapentin had an NNT of 3.2 in postherpetic neuralgia; in painfuldiabetic neuropathy it had an NNT of 3.8, while carbamazepine had an NNTof 2.3 and phenytoin had an NNT of 2.1 (Wiffen P et al., THE COCHRANEDATABASE OF SYSTEMATIC REVIEWS 2005 (3):CD001133, 2005). Other testedanticonvulsants appeared to be less effective. It is noted thatanticonvulsants, as tricyclic antidepressants, frequently producesignificant adverse effects in patients.

Opioid analgesics: A recent meta-analysis of the efficacy and safety ofopioid agonists in the treatment of non-malignant neuropathic painshowed marginal to no efficacy in short-term (24 hour) studies, andmarginal efficacy in intermediate-term (8-56 day) studies (Eisenberg Eet al., JAMA 293:3043-3052, 2005). The drugs studied were morphine,oxycodone, methadone, and levorphanol. A study of levorphanol found thatpatients with postherpetic neuralgia had an average 14% reduction inpain with a low dose, and a 33% reduction with a high dose, though 31%of the subjects dropped out of the study due to drug side effects(Rowbotham M C et al., NEW ENGLAND JOURNAL OF MEDICINE 348:1223-1232,2003). All the opioid drugs commonly produced significant butnon-life-threatening adverse effects.

Topical lidocaine: A topically applied patch containing 5% lidocaine iscommonly used to treat localized peripheral neuropathic pain. Clinicalstudies have shown that this treatment results in modest reductions ofpain for many patients (e.g., Argoff C E et al., CURRENT MEDICALRESEARCH AND OPINION 20 Suppl 2:S21-S28, 2004). One controlled studyfound an NNT of 2 in postherpetic neuralgia (Hempenstall K et al., PLOSMEDICINE 2:e164, 2005). To remain effective, the patches must be changedseveral times per day. The patches cause numbness of the contacted skin,and commonly cause skin irritation, and usually do not relieve severepain.

Topical capsaicin: An analysis of two studies on the use of topicalcapsaicin cream to treat postherpetic neuralgia found a low efficacyrate, with an NNT value of 3.26 (Hempenstall K et al., PLOS MEDICINE2:e164, 2005). It is noted that placebo-controlled studies withcapsaicin are compromised due to the clearly noticeable sensations(including pain) produced in the skin by capsaicin; thus, perceivedefficacy of capsaicin may benefit from a placebo effect.

Many other systemic and local treatments are used in attempts to relieveperipheral neuropathic pain, generally with no more than moderatesuccess. Recently, subcutaneously injected botulinum-A toxin has beentried in a small number of patients with trigeminal neuralgia (PiovesanE J et al., NEUROLOGY 66:1458-1459, 2006) and in a single patient withpostherpetic neuralgia (Liu H T et al., PAIN MEDICINE 7:89-91, 2006).The patient with postherpetic neuralgia reported pain relief for severalweeks after numerous injections, followed by a recurrence of pain atpre-treatment levels. The patients with trigeminal neuralgia reportedtransient low to moderate pain relief following multiple injections,with side effects including muscle weakness.

It is thus apparent that currently available treatments for peripheralneuropathic pain have only low to moderate efficacy, and many patientsare left without significant pain relief. The lack of adequate painrelief for millions of people with peripheral neuropathic pain, as wellas for those with other types of pain, represents a great unmet medicalneed.

SUMMARY OF THE INVENTION

Accordingly, it is a primary object of the invention to providepharmaceutical compositions, methods, and drug delivery systems fortreating pain, including allodynia, hyperalgesia, paresthesia,discomfort, itching, and neuropathic pain.

In a preferred embodiment of the invention, a method is provided inwhich pain is treated in an individual afflicted with such a condition,comprising administering to the painful region, to tissues adjacent tothe painful region, or to tissues in or adjacent to the region fromwhich the pain is referred, a therapeutically effective amount of apharmaceutical composition comprising a pharmaceutically acceptablegallium compound and a carrier suitable for local administration.

Additional objects, advantages and novel features of the invention willbe set forth in part in the description which follows, and in part willbecome apparent to those skilled in the art upon examination of thefollowing, or may be learned by practice of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Before the present compositions, methods, and drug delivery systems ofthe invention are disclosed and described, it is to be understood thatthis invention is not limited to specific formulations, i.e., specificcarrier materials or the like, to specific dosage regimens, or tospecific drug delivery systems, as such may vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only and is not intended to belimiting.

As used herein (which includes the specifications and the claims), theterm “pain” encompasses the usual meanings of the word, and alsoencompasses the usual meanings of “itching,” “allodynia,”“hyperalgesia,” “paresthesia,” and “discomfort,” as well as combinationsof these.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a gallium compound” includes mixtures of suchcompounds; reference to “a carrier” includes mixtures of two or morecarriers; and the like.

The term “topical administration” is used herein in its conventionalsense to mean delivery of a pharmacologically active agent to the skinor mucosa, including the mucosa of the mouth, nasal and sinus cavities,eyes, gastrointestinal tract, bladder, urethra, and vagina.

The term “local administration” as used herein encompasses the meaningof “topical administration,” and also includes administration tospatially restricted portions of the body, including portions of theskin, muscle, eyes, and other tissues and organs, and combinations ofthese.

The term “patient” as used herein is meant to include a human or aveterinary patient. Within the context of the present invention,veterinary patients include both mammalian and non-mammalian veterinarypatients, the latter including such veterinary patients as, for example,lizards and birds.

The terms “active agent,” “drug,” and “pharmacologically active agent”are used interchangeably herein to refer to a chemical material orcompound that, when administered to an organism (human or animal),induces a desired pharmacologic effect, such as a reduction in pain.

The terms “to treat” and “treatment” as used herein encompass the usualmeanings of these terms plus the usual meanings of the terms “toprevent” and “prevention”. Thus, for example, “treatment” ofpostherpetic neuralgia, as the term “treatment” is used herein,encompasses both prevention of postherpetic neuralgia in a predisposedindividual and treatment of postherpetic neuralgia in an individual whohas such a disease.

By the term “effective” amount of a drug is meant a sufficient amount ofa compound to provide the desired effect and performance at a reasonablebenefit/risk ratio as attends any medical treatment.

The term “vehicle” or “carrier” as used herein refers to a vehiclesuitable for administration of a drug, and includes any such materialsknown in the art, e.g., any liquid or non-liquid carrier, gel, cream,ointment, lotion, paste, emulsifier, solvent, liquid diluent, solid,wax, powder, or the like, that is stable with respect to all componentsof the pharmaceutical formulation, and is appropriate and safe for theparticular mode of administration for which it is intended (e.g.,topical, subcutaneous, intramuscular, intravenous, intraocular).

This invention comprises pharmaceutical compositions suitable for thelocalized administration of gallium, and devices and methods for usingsuch compositions to treat pain. Formulations appropriate forapplication to skin, mucous membranes, the eyes, or other external orinternal portions of the body may be prepared in the practice of theinvention.

Treatment is applicable to human and veterinary patients, includingparticularly mammals and birds. Mammalian veterinary subjects include,without limitation, dogs, cats, and members of the Equidae, Bovidae,Caprinae, and Suidae. Veterinary subjects also include, withoutlimitation, reptiles, amphibians, and fish.

The locally administrable pharmaceutical compositions comprise a carrierand a pharmaceutically acceptable gallium compound. Carriers suitablefor localized administration include, for example, topical carriers fortopical administration, subcutaneous carriers for subcutaneousinjection, intraocular carriers for intraocular administration, and thelike, as are well known in the art. Locally administrable pharmaceuticalcompositions suitable for topical administration, which is a preferredmeans of administration, comprise a topical carrier and apharmaceutically acceptable gallium compound.

A topical carrier, as noted above, is one that is generally suited totopical drug administration and includes any such materials known in theart. The topical carrier is selected so as to provide the composition inthe desired form, e.g., as a liquid, lotion, cream, paste, gel, gum,powder, ointment, or soluble solid, and may be comprised of a materialof either naturally occurring or synthetic origin, or of a combination.It is essential that the selected carrier not adversely affect theactive agent or other components of the topical formulation. Examples ofsuitable topical carriers for use herein include water, alcohols andother nontoxic organic solvents, glycerin, mineral oil, silicone,petroleum jelly, petrolatum, lanolin, fatty acids, sugars, vegetableoils, parabens, waxes, and the like. The composition of the inventionmay be administered in the form of a shampoo, in which case conventionalcomponents of such a formulation are included as well, e.g.,surfactants, conditioners, viscosity modifying agents, humectants, andthe like. The composition of the invention may also be prepared, withoutlimitation, as lozenges, troches, candies, orally disintegratingtablets, sublingual tablets, buccal tablets, buccal patches, chewinggums, and the like, as well as suppositories and the like, as nasalsprays and the like, as eye drops and the like, as lip balms and thelike, and as tablets and capsules and the like.

Particularly preferred formulations herein are colorless, odorlessointments, lotions, creams, and gels.

Ointments are semisolid preparations that are typically based onpetrolatum or other petroleum derivatives. The specific ointment base tobe used, as will be appreciated by those skilled in the art, is one thatwill provide for optimum drug delivery, and, preferably, will providefor other desired characteristics as well, e.g., emolliency or the like.As with other carriers or vehicles, an ointment base should be inert,stable, nonirritating, and nonsensitizing. As explained in REMINGTON:THE SCIENCE AND PRACTICE OF PHARMACY, 19th Ed. (Easton, Pa.: MackPublishing Co., 1995), at pages 1399-1404, ointment bases may be groupedin four classes: oleaginous bases, emulsifiable bases, emulsion bases,and water-soluble bases. Oleaginous ointment bases include, for example,vegetable oils, fats obtained from animals, and semisolid hydrocarbonsobtained from petroleum. Emulsifiable ointment bases, also known asabsorbent ointment bases, contain little or no water and include, forexample, hydroxystearin sulfate, anhydrous lanolin, and hydrophilicpetrolatum. Emulsion ointment bases are either water-in-oil emulsions oroil-in-water emulsions, and include, for example, cetyl alcohol,glyceryl monostearate, lanolin, and stearic acid. Preferredwater-soluble ointment bases are prepared from polyethylene glycols ofvarying molecular weight; again, reference may be had to REMINGTON: THESCIENCE AND PRACTICE OF PHARMACY, 20^(th) Edition (Gennaro A R, Ed.,Lippincott, Williams and Wilkins, 2000) for further information. Aparticularly preferred ointment base for use in conjunction with thepresent invention contains a hydrophilic petrolatum such as that whichmay be obtained under the trademark Aquaphor® from Beiersdorf, Inc.(Wilton, Conn.).

Lotions are preparations to be applied to the skin surface withoutfriction, and are typically liquid or semiliquid preparations in whichsolid particles, including the active agent, are present in a water oralcohol base. Lotions are usually suspensions of solids, and preferably,for the present purpose, comprise a liquid oily emulsion of theoil-in-water type. Lotions are preferred formulations herein fortreating large body areas, because of the ease of applying a more fluidcomposition. It is generally necessary that the insoluble matter in alotion be finely divided. Lotions will typically contain suspendingagents to produce better dispersions as well as compounds useful forlocalizing and holding the active agent in contact with the skin, e.g.,methylcellulose, sodium carboxymethylcellulose, or the like.

Creams containing the selected gallium compound are, as known in theart, viscous liquid or semisolid emulsions, either oil-in-water orwater-in-oil. Cream bases are water-washable, and contain an oil phase,an emulsifier, and an aqueous phase. The oil phase, also sometimescalled the “internal” phase, is generally comprised of petrolatum and afatty alcohol such as cetyl or stearyl alcohol; the aqueous phaseusually, although not necessarily, exceeds the oil phase in volume, andgenerally contains a humectant. The emulsifier in a cream formulation,as explained in Remington (2000) supra, is generally a nonionic,anionic, cationic, or amphoteric surfactant.

Gel formulations are preferred for application to the scalp. As will beappreciated by those working in the field of topical drug formulation,gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe carrier liquid, which is typically aqueous, but also, preferably,contain an alcohol and, optionally, an oil.

The gallium compositions of the invention may also be formulated usingliposomes. Such formulations may be particularly advantageous forsustained release or delayed release compositions. Other formulationsfor sustained release or delayed release may also be employed.

Shampoos for treating peripheral neuropathic pain may be formulated withthe selected gallium compound and standard shampoo components, i.e.,cleansing agents, thickening agents, preservatives, and the like, withthe cleansing agent representing the primary ingredient, typically ananionic surfactant or a mixture of an anionic and an amphotericsurfactant.

Various additives, known to those skilled in the art, may be included inthe topical or other local formulations of the invention. For example,solvents may be used to dissolve certain drug substances. Other optionaladditives include skin permeation enhancers, opacifiers, colorants,fragrances, flavoring agents, anti-oxidants, gelling agents, thickeningagents, stabilizers, preservatives, and the like. The topical or otherlocal compositions of the invention may be also optionally comprise oneor more other active agents, including, without limitation,pain-reducing agents, analgesics, anesthetics, anti-inflammatory agents,anti-seizure agents, antidepressants, anticancer agents, antibiotics,antimicrobial agents, antibacterial agents, antifungal agents, antiviralagents, antiparasitic agents, and anthelmintic agents.

In the preferred topical and other local formulations of the invention,the gallium compound is present in an amount such that the galliumcontent is generally about 0.00001 to about 15 percent by weight of theformulation, preferably about 0.001 to about 0.5 percent, and mostpreferably about 0.01 to about 0.1 percent.

As an example of a pharmaceutically acceptable aqueous solution of theinvention, gallium nitrate is dissolved in water, at a galliumconcentration of from about 0.01 to about 15 wt. % Ga, preferably fromabout 1 to about 10 wt. % Ga, and most preferably from about 2 to about7 wt. % Ga. As another example of a pharmaceutically acceptable aqueoussolution of the invention, which is preferred, gallium maltolate isdissolved in water at a concentration of about 0.0005 to about 1 wt. %Ga, preferably about 0.01 to about 0.16 wt. % Ga. Other excipients,carriers, stabilizers, solubilizers, buffers, pH adjusters, permeationenhancers, absorption enhancers, thickeners, active agents,preservatives, etc. may be added to the solutions. An example of apossible additive is DMSO.

The topical compositions of the invention may also be delivered to theskin using “transdermal”-type patches, wherein the drug composition iscontained within a laminated structure that serves as a drug deliverydevice to be affixed to the skin. In such a structure, the drugcomposition is contained in a layer, or “reservoir,” underlying an upperbacking layer. The laminated structure may contain a single reservoir,or it may contain multiple reservoirs. In one embodiment, the reservoircomprises a polymeric matrix of a pharmaceutically acceptable contactadhesive material that serves to affix the system to the skin duringdrug delivery. Examples of suitable skin contact adhesive materialsinclude, but are not limited to, polyethylenes, polysiloxanes,polyisobutylenes, polyacrylates, polyurethanes, and the like. Theparticular polymeric adhesive selected will depend on the particulardrug, vehicle, etc., i.e., the adhesive must be compatible with allcomponents of the drug-containing composition. In an alternativeembodiment, the drug-containing reservoir and skin contact adhesive arepresent as separate and distinct layers, with the adhesive underlyingthe reservoir that, in this case, may be either a polymeric matrix asdescribed above, or it may be a liquid or hydrogel reservoir, or it maytake some other form.

The backing layer in these laminates, which serves as the upper surfaceof the device, functions as the primary structural element of thelaminated structure, and provides the device with much of itsflexibility. The material for the backing material should be selected sothat it is substantially impermeable to the drug and to any othercomponents of the drug-containing composition, thus preventing loss ofany components through the upper surface of the device. The backinglayer may be either occlusive or non-occlusive, depending on whether itis desired that the skin become hydrated during drug delivery. Thebacking is preferably made of a sheet or film of a preferably flexibleelastomeric material. Examples of polymers that are suitable for thebacking layer include polyethylene, polypropylene, polyesters, and thelike.

During storage and prior to use, the laminated structure includes arelease liner. Immediately prior to use, this layer is removed from thedevice to expose the basal surface thereof, either the drug reservoir ora separate contact adhesive layer, so that the system may be affixed tothe skin. The release liner should be made from a drug/vehicleimpermeable material.

Such devices may be fabricated using conventional techniques, known inthe art, for example by casting a fluid admixture of adhesive, drug, andvehicle onto the backing layer, followed by lamination of the releaseliner Similarly, the adhesive mixture may be cast onto the releaseliner, followed by lamination of the backing layer. Alternatively, thedrug reservoir may be prepared in the absence of drug or excipient, andthen loaded by “soaking” in a drug/vehicle mixture.

As with the other topical formulations of the invention, the drugcomposition contained within the drug reservoirs of these laminatedsystem may contain a number of components. In some cases, the drug maybe delivered “neat,” i.e., in the absence of additional liquid. In mostcases, however, the drug will be dissolved, dispersed, or suspended in asuitable pharmaceutically acceptable vehicle, typically a solvent orgel. Other components that may be present include preservatives,stabilizers, surfactants, and the like.

Formulations employed for transdermal patches of the invention typicallycontain about 0.0005 to about 10 wt. % Ga, preferably about 0.01 toabout 2 wt. % Ga, and most preferably about 0.05 to about 0.5 wt. % Ga.

The topical formulations, including those used in conjunction with thelaminated drug delivery systems, may in addition contain a skinpermeation enhancer. Because the inherent permeability of the skin tosome drugs may be too low to allow therapeutic levels of the drug topass through a reasonably sized area of unbroken skin, it is necessaryto co-administer a skin permeation enhancer with such drugs. Suitableenhancers are well know in the art and include, for example,dimethylsulfoxide (DMSO), dimethyl formamide (DMF),N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C₁₀ MSO), C₂-C₆alkanediols, and the 1-substituted azacycloheptan-2-ones, particularly1-n-dodecylcyclazacycloheptan-2-one (available under the trademarkAzone® from Whitby Research Incorporated, Richmond, Va.), alcohols,bases, and the like.

In a methodological embodiment of the invention, pain, includingperipheral neuropathic pain, is treated by locally administering apharmaceutical composition comprising gallium to a painful region, totissues adjacent to the painful region, or to tissues in or adjacent tothe region from which the pain is referred. By “adjacent” is meantwithin a few millimeters to within a few centimeters. A preferred meansof local administration is topical administration. In thismethodological embodiment, a topical pharmaceutical compositioncomprising gallium is topically administered to the skin or mucousmembrane at a region of pain, or at a region in which pain is present inunderlying tissues. Topical administration may also be applied to aregion of skin or mucus membrane from which pain is referred, or that issuperior to underlying tissues from which pain is referred. Treatablepain may originate, or seem to originate, in the skin or mucousmembrane, or in underlying tissue or tissues. The underlying tissue ortissues may include, without limitation, muscle, tendon, ligament, bone,cartilage, nerve, organ, vascular, follicular, glandular, connective,and joint tissues. Treatable individuals include humans, but alsoinclude veterinary subjects. When used in a preventive method,susceptible regions are treated prior to the occurrence of pain onregions known to be susceptible to pain in a particular individual.

The composition may be applied by any practical, medically acceptablemeans. For example, application may be made using fingers, swabs,droppers, squeeze tubes or bottles, compresses, patches, osmotic pumps,aerosols, means for injection, or other means. In the treatment of pain,including peripheral neuropathic pain, it will be recognized by thoseskilled in the art that the optimal quantity and spacing of individualdosages of the gallium compositions of the invention will be determinedby the nature and extent of the condition being treated, the form, routeand site of administration, and the particular individual undergoingtreatment, and that such optimums can be determined by conventionaltechniques. It will also be appreciated by one skilled in the art thatthe optimal dosing regimen, i.e., the number of doses of a galliumcomposition of the invention, can be ascertained using conventionalcourse of treatment determination tests. Generally, a dosing regimenwill involve administration of the selected formulation at least oncedaily, and preferably one to four times daily, until the pain, itching,paresthesia, or other symptoms have subsided. In some cases, a singledose will suffice, while in other cases dosing may continue for days,weeks, months, years, or indefinitely, to maintain adequate pain relief.

The area of the body to be treated may also be soaked in a solution ofthe invention. Such soaking may be particularly useful in treating painof the hands, arms, feet, or legs. Soaking may be continuous for as muchas several days, or may be applied daily for about 1 minute to about 12hours, preferably for about 15 minutes to 6 hours, and most preferablyfor about 1 hour to 3 hours. An example of such a soaking solution isgallium maltolate dissolved in water at a gallium concentration of about0.0005 to about 1 wt. % Ga, preferably about 0.01 to about 0.16 wt. %Ga. Excipients, carriers, stabilizers, solubilizers, buffers, pHadjusters, permeation enhancers, absorption enhancers, thickeners,active agents, preservatives, colorants, fragrances, etc. may be addedto the solution. The soaking solution may be at room temperature or atother comfortable temperatures, including comfortably elevatedtemperatures.

Other forms of administration of the compositions of the inventioninclude, without limitation, buccal, sublingual, lingual, intra-lingual,nasal, intra-sinus, intraocular, topical ocular, oral, topical to thelips, vaginal, urethral, perianal, instillation into the bladder,rectal, otic, local perfusion into tissue by injection, subcutaneous,intramuscular, peritoneal, intravenous, intra-arterial, and byinhalation.

Typical topical doses of the gallium composition, expressed as theamount of contained elemental gallium per square centimeter of surfacearea (as on the skin or mucosal surface) are, for example, about0.000001 to 1 mg, preferably about 0.0001 to 0.1 mg, and more preferablyabout 0.0005 to 0.005 mg; such doses are typically administered, forexample, once per week to six times per day, and more typically one tofour times per day. When administered continuously, as by the use of apatch or osmotic pump, typical daily doses of the gallium composition,expressed as the amount of contained elemental gallium per squarecentimeter of surface area (as on the skin) are, for example, about0.000005 to 5 mg, preferably about 0.0005 to 0.5 mg, and more preferablyabout 0.001 to 0.05 mg. Typical doses of the gallium composition,expressed as the amount of contained elemental gallium, whenadministered to a spatially restricted internal portion of the body, asby injection or other means, are, for example, about 0.000001 to 5 mg,preferably about 0.002 to 0.5 mg, and more preferably about 0.01 to 0.1mg per cubic centimeter of tissue.

Pain treatable by this invention (which includes itching, allodynia,hyperalgesia, paresthesia, and discomfort, as well as combinations ofthese) is not restricted to any particular cause, disease, or disorder.Examples of treatable pain include, without limitation, neuropathicpain; pain associated with inflammation, including that from arthritis,hemorrhoids, or plantar fasciitis as examples; pain associated withtrauma, injury, surgery, infection (e.g., bacterial, viral, fungal,protozoan, helminthic, parasitic), neoplasia, hyperplasia, radiation,irritation, or burns; pain associated with locally or systemicallycontacted toxins; pain associated with insect, spider, or animal bitesor stings; and pain associated with allergic or other sensitivityreactions, pruritus, and the like. Furthermore, peripheral neuropathicpain treatable by this invention is not restricted to any particularcause, disease, or disorder. Examples of treatable peripheralneuropathic pain include, without limitation, painful diabeticneuropathy; infection-related neuropathic pain, including HIV-relatedneuropathic pain, herpes zoster related neuropathic pain, and herpessimplex related neuropathic pain; postherpetic neuralgia; facialneuralgia, including trigeminal neuralgia; cancer-associated neuralgia,including neuralgia caused by neuronal tumors, tumor infiltration ofneurons, tumors pressing on neurons, chemotherapy, surgery, andradiation treatment; pain associated with trauma, including that causedby surgery; pain associated with root avulsions, nerve entrapment,carpal tunnel syndrome, or ischemic nerve injury; painful traumaticmononeuropathy or polyneuropathy; distal sensory polyneuropathy; complexregional pain syndrome; and neuropathy caused by systemic or locallycontacted toxins.

Gallium compounds usable in this invention include, without limitation,gallium nitrate, gallium sulfate, gallium citrate, gallium chloride,gallium complexes of 3-hydroxy-4-pyrones including gallium maltolate,gallium pyridinones, gallium tartrate, gallium succinate, galliumgluconate, gallium palmitate, gallium 8-quinolinolate, galliumporphyrins including gallium(III) protoporphyrin IX, galliumtransferrin, bis(2-acetylpyridine 4N-dimethylthiosemicarbazone)gallium(III)-gallium(III) tetrachloride, gallium pyridoxal isonicotinoylhydrazone, gallium complexes of kenpaullone and its derivatives, and anyother pharmaceutically acceptable gallium inorganic salts, organicsalts, inorganic compounds, chelates, coordination compounds, complexes,and organometallic compounds. Gallium maltolate,tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium, is a preferred galliumcompound of the invention; this compound is described, for example, inU.S. Pat. No. 5,981,518 to Bernstein.

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of drug formulation, which are withinthe skill of the art. Such techniques are fully explained in theliterature. See, for example, REMINGTON: THE SCIENCE AND PRACTICE OFPHARMACY (2000), cited supra, as well as Goodman & Gilman's THEPHARMACOLOGICAL BASIS OF THERAPEUTICS, 9th Ed. (New York: McGraw-Hill,1996) and Ansel et al., PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERYSYSTEMS, 6^(th) Ed. (Media, Pa.: Williams & Wilkins, 1995). Any suitablepharmaceutical formulations that comprise pharmaceutically acceptablegallium compositions may be utilized in the practice of the invention.

All patents, patent documents, and publications cited herein are herebyincorporated by reference in their entirety for their disclosureconcerning any pertinent information not explicitly included herein.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, theforegoing description, as well as the examples that follow, are intendedto illustrate and not limit the scope of the invention. Other aspects,advantages, and modifications will be apparent to those skilled in theart to which the invention pertains.

EXPERIMENTAL

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the compositions of the invention. The examples areintended as non-limiting examples of the invention. While efforts havebeen made to ensure accuracy with respect to variables such as amounts,temperature, etc., experimental error and deviations should be takeninto account. Unless indicated otherwise, parts are parts by weight,temperature is degrees Celsius, and pressure is at or near atmospheric.All components were obtained commercially unless otherwise indicated.

Example 1 Topical Formulation of Gallium Maltolate I

A gallium maltolate formulation for topical application to the skin wasprepared at room temperature with the following composition:

Gallium maltolate: 0.25 wt %

Aquaphor®: 89.75 wt %

Water (sterile, deionized): 10 wt %

First, 5 g of gallium maltolate powder was stirred in 200 g of water for120 min. This solution/suspension was then slowly added to 1795 g ofAquaphor®, over a period of 10 min, with continuous stirring. Stirringthen continued for an additional 30 minutes, until a homogeneous whitecream was produced.

Example 2 Topical Formulation of Gallium Maltolate II

A gallium maltolate formulation for topical application to the skin wasprepared at room temperature with the following composition:

Gallium maltolate: 0.5 wt %

Aquaphor®: 49.5 wt %

Water (sterile, deionized): 50 wt %

First, 4 g of gallium maltolate powder was stirred in 400 g of water for120 min. This solution was then slowly added to 396 g of Aquaphor®, overa period of 10 min, with continuous stirring. Stirring then continuedfor an additional 30 minutes, until a homogeneous white cream wasproduced.

Example 3 Use of Gallium Maltolate Cream to Treat Postherpetic Neuralgia

A 100-year-old woman had been experiencing postherpetic neuralgia witherythema on the left side of her face for approximately three years. Thepain was so severe that it interfered with sleep and other dailyactivities. During that period she had tried numerous systemicanalgesics to relieve the pain, including amitriptyline 25 mg BID,methadone 5 mg BID, carbamazepine 100 mg BID, gabapentin 200 mg QD,oxycodone 20 mg BID, naproxen, acetaminophen, and intravenous hydrogenperoxide. She had also tried topically applied medications, includinglidocaine 5% patches. None of these treatments produced significant painrelief. She then began treatment using the topical gallium maltolateformulation of Example 1, above. This formulation was applied threetimes per day to the affected area, at about 8 AM, 1 PM, and 9 PM, everyday for four weeks. The formulation was administered by dipping afingertip lightly into the formulation, and then smearing theformulation from the fingertip onto the affected area. Approximately 15minutes following the initial administration, significant reduction ofpain was noticed. Three days following the start of treatment, the painhad been further reduced, as had the erythema. The reduction in pain anderythema continued for the entire four week treatment period. No adverseeffects from the treatment were observed. The patient reported that thepain relief she experienced while using topical gallium maltolate hadgreatly improved her quality of life.

Example 4 Use of Gallium Maltolate Cream to Treat Pain and ItchingAssociated with Vaginal Inflammation

A 49-year-old woman had vaginal inflammation associated with moderate tosevere pain, itching, and erythema. Topical miconazole was ineffectiveand irritating, and topical benzocaine had little effect. Light topicalapplication of the gallium maltolate formulation of Example 2 to thevagina and immediately adjacent external region relieved the pain,itching, and erythema within 15 minutes. Continued use of theformulation three times per day eliminated the vaginal inflammation intwo days. No adverse effects from the treatment were observed.

Example 5 Use of Gallium Maltolate Cream to Treat Inflamed PainfulSpider Bites

A 100-year-old woman received two spider bites on the inner surface ofher lower left arm. The bites became inflamed, with erythema, edema, andsevere pain. The pain was severe enough to disrupt sleep. The womanapplied the topical gallium maltolate formulation of Example 1 to theinflamed, painful areas of skin at and around the bites. The formulationwas administered by dipping a fingertip lightly into the formulation,and then smearing the formulation from the fingertip onto the affectedareas. The pain was entirely relieved with ten minutes followingapplication of the gallium maltolate formulation, and the erythema andedema subsided within an hour. No adverse effects from the treatmentwere observed.

Example 6 Use of Gallium Maltolate Cream to Treat Pain and InflammationAssociated with a Herpes Simplex Lesion

A 48-year-old woman developed an active herpes simplex lesion (coldsore), 5 mm across, just above her left upper lip. About 24 hours afterit was first noticed, the lesion had become a painful weeping abscessthat was very painful to the touch. A small amount of the formulation ofExample 2 was applied to the lesion at this time, and was then appliedtwice per day thereafter for four days. Twelve hours after the initialapplication, the pain and inflammation associated with the lesion weregreatly reduced. After four days, all pain and discomfort associatedwith the lesion had gone, and the lesion itself had largely healed, withalmost no remaining inflammation. The patient said that such lesionsnormally take more than ten days to resolve, with pain being presentuntil full resolution.

I claim:
 1. A method for treating pain associated with hemorrhoids,plantar fasciitis, radiation, or locally or systemically contactedtoxins in a subject in need thereof, comprising administering to thepainful region, to tissues adjacent to the painful region, or to tissuesin or adjacent to the region from which the pain is referred, atherapeutically effective amount of a pharmaceutical compositioncomprising gallium 8-quinolinolate and a carrier suitable for localadministration.
 2. The method of claim 1, wherein the pharmaceuticalcomposition is selected from the group consisting of an ointment, alotion, a cream, and a gel.
 3. The method of claim 1, wherein thepharmaceutical composition is a shampoo.
 4. The method of claim 1,wherein the pharmaceutical composition is present in a drug reservoircontained within a laminated patch adapted to be affixed to the skin. 5.The method of claim 1, wherein the pharmaceutical composition isselected from the group consisting of a lozenge, a troche, a candy, acapsule, a tablet, an orally disintegrating tablet, a sublingual tablet,a buccal tablet, a buccal patch, a nasal spray, an aerosol, a lip balm,and chewing gum.
 6. The method of claim 1, wherein the pharmaceuticalcomposition is in the form of a suppository.
 7. The method of claim 1,wherein the pharmaceutical composition is in the form of eye drops. 8.The method of claim 1, wherein the pharmaceutical composition isadministered topically to the skin.
 9. The method of claim 1, whereinthe pharmaceutical composition is administered. topically to the mucousmembranes.
 10. The method of claim 1, wherein the pharmaceuticalcomposition is administered to the painful region.
 11. The method ofclaim 1, wherein the pharmaceutical composition is administered bysoaking.
 12. The method of claim 1, wherein the means of administrationof the pharmaceutical composition is selected from the group consistingof buccal, sublingual, lingual, intra lingual, nasal, intra-sinus,intraocular, topical ocular, oral, topical to the lips, vaginal,urethral, perianal, instillation into the bladder, rectal, otic, localperfusion into tissue by injection, subcutaneous, intramuscular,peritoneal, and inhalation.
 13. The method of claim 1, wherein thegallium content of the pharmaceutical composition represents about0.00001 to about 15 percent by weight of the composition,
 14. The methodof claim 1, wherein the gallium content of the pharmaceuticalcomposition represents about 0.001 to about 0.5 percent by weight of thecomposition.
 15. The method of claim 1, wherein the gallium content ofthe pharmaceutical composition represents about 0.01 to about 0.1percent by weight of the composition.
 16. The method of claim 1, whereinthe pharmaceutical composition comprises one or more additional activeagents.